The present invention relates to multi-unitary pharmaceutical preparations containing piroxicam for oral administration. The formulations comprise a spherical inert core, constituted by starch and sugars, coated with a layer containing the active ingredient in micronized form, which is mixed with pharmaceutically acceptable inert excipients, whose proportions are suitable for allowing the disaggregation of the dosage forms and the intended dissolution of the active ingredient, this layer in turn being coated with an insulating polymeric layer, applying lastly a gastroresistant or enteric external layer, of suitable thickness, in order to guarantee the integrity of the product until it reaches the proximal part of the small intestine, where the formulation will be disaggregated to facilitate the absorption of the piroxicam. The pellets produced according to the invention are placed in hard gelatine capsules and administered under this form. The invention allows the oral administration of piroxicam, preventing the adverse gastrointestinal disturbances and ulcerogenic effects of piroxicam generally associated with chronic use, because the piroxicam is only delivered at the proximal portion of small intestine and this is an advantage in relation to the other pharmaceutical preparations of piroxicam for oral administration. Besides, the pharmaceutical product prepared according to the invention is free from organic solvents and/or the impurities generally associated to them, because the application of the different layers exclusively requires aqueous solvents. This aspect constitutes a technological advantage, since the manufacturing process is safe, because there is no toxicity risk to operators or explosion risks, and it is much more ecological, because there is no possibility of environmental contamination caused by organic solvents leaking into the atmosphere. Finally, it is much safer for the patient, because there is no need to consider solvent and/or residual impurities associated to them, which is a considerable advantage in terms of public health. For the manufacture of the product, only one equipment is requiredxe2x80x94a fluid bed equipment with an inner partition device (wurster). The products obtained by extrusion/spheronization, by rotogranulation or by xe2x80x9cpowder coatingxe2x80x9d are completely outside the scope of this invention. The products obtained are stable for a period of time compatible with pharmaceutical requirements and present gastroresistance and dissolution characteristics generally adapted to the period of validity established for pharmaceutical products (i.e. 3 years).
Piroxicam, whose chemical name is N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxyamido-1,1-dioxide, is a nonsteroidal anti-inflammatory drug (NSAID) described and claimed by J. G. Lombardino in the patent U.S. Pat. No. 3,591,584. It possesses excellent anti-inflammatory and analgesic properties and is widely used in the treatment of arthritic and rheumatic diseases, namely osteoarthritis and rheumatoid arthritis. For these indications, it is normally administered orally. However, piroxicam has various side effects, including gastrointestinal disorders and ulcerogenic effects generally associated with its chronic use. In chronic use, with high dosages and especially in the elderly, NSAIDs can induce stomach ulcers that may be dangerous. Such ulcers generally show little or few symptoms and may cause serious bleeding when undetected. Accordingly, when inflammatory symptoms become less severe, it is often desirable to apply piroxicam topically. Nevertheless, in acute cases, oral or rectal administration is most suitable. However, rectal administration is not functional, is very uncomfortable and is not favoured by patients. It is also well known that oral administration is the best way of making patients follow the therapeutic treatment. For this reason, various efforts have been made to minimize the adverse effects of NSAIDs when administered orally. Several authors have tried to solve the problem of the gastric lesions produced by oral NSAID pharmaceutical preparations:
EP-0 288 138 describes multi-particulate pharmaceutical compositions containing water-insoluble drugs dispersed in a controlled release matrix. Preferred drugs are NSAIDs, especially calcium fenprofen, ibuprofen, ketoprofen, naxoprofen, sodium diclofenac, fenbufen, flurbiprofen, indomethacin, oxyphenbutazone, phenylbutazone and piroxicam. These pharmaceutical compositions are multi-unitary and drug release occurs in the gastric region, contrary to what is intended with the present invention.
EP-0123520 describes processes for preparing piroxicam salts and pharmaceutical dosage forms from which the piroxicam is rapidly absorbed in the gastrointestinal tract after administration.
U.S. Pat. No. 5,654,002 describes a process for the production of conventional piroxicam tablets.
U.S. Pat. No. 5,015,481 describes a pharmaceutical tablet composition, which is an admixture of an NSAID, diclofenac or piroxicam, a prostaglandin and hydroxypropylmethylcellulose in order to maintain the prostaglandin in a therapeutically active amount to allow the prevention of NSAID-induced ulcers.
U.S. Pat. Nos. 5,601,843 and 5,698,225 describe pharmaceutical tablet compositions including a core of an NSAID selected between diclofenac and piroxicam which is surrounded by a mantle coating of a prostaglandin, wherein an intermediate coating can also be present between the NSAID core and the prostaglandin mantle.
Prostaglandins are generally considered to be highly unstable and difficult to provide in orally-available stabilized forms. The association of prostaglandins with NSAIDs is a factor of increased stability for both drugs. On the other hand, this association implies the administration of two active ingredients instead of just one, which represents an inadvisable overload for the metabolism of the patient.
The present invention describes multi-particulate gastroresistant coating dosage forms to prevent the delivery of the piroxicam in the gastric compartment and allow its release at the proximal portion of small intestine, preventing gastric lesions resulting from the direct contact of piroxicam with gastric mucous. The multi-unitary dosage form, after dissolution of the enteric coating, rapidly disperses and releases the piroxicam, which is immediately absorbed through the membranes of the small intestine. The present invention concerns stable multi-unitary pharmaceutical compositions for oral administration consisting of gastroresistant pellets free from residues of organic solvents and the impurities associated to them. This piroxicam formulation is new, taking into account the current state of the art. Its manufacturing process involves the use of only one equipment for all the stages of its production, which is a fluid bed equipment with an inner partition device (wurster). Thus, the present invention describes pellet formulations composed of an inert core coated with a layer containing the active ingredient piroxicam, coated in turn with an intermediate layer which is coated finally with an external gastroresistant or enteric coating layer of a minimum thickness of 20 xcexcm. The presence of the intermediate layer is important for the rapid dissolution of the final product. The pellets obtained have spherical symmetry and their surface is perfectly flat, when observed by scanning electronic microscopy (S.E.M.), contrary to what happens when other techniques are used, like powder coating, extrusion/spheronization or coating in conventional coating pans. In addition, the fact that the products are manufactured without the aid of organic solvents makes them safer for patients and for operators who manufacture and handle them. The manufacturing process does not cause environmental pollution problems, which are becoming increasingly essential to avoid. Moreover, the process for manufacturing these new formulations has technical as well as economic advantages. In fact, all the stages of the manufacturing process use the same equipment, which represents less contact for the operator with the product, contrary to what generally happens with other processes which require the transfer of the pellets from the extruder/spheronizer to coating pans or fluid bed equipments in order to be coated. Neither does it involve various equipments of restricted use and a high price, which would have to be reflected in the final price of the product to consumers and be borne by patients who need the medication.
A particular benefit of the invention is that it provides a safe method for treating inflammation with piroxicam without gastric sequelae, it permits chronic use and/or high dosages and, in particular, use by the elderly. Obviously, the present invention could be applied to other high potency NSAIDs.
The present invention describes multi-unitary pharmaceutical dosage forms containing piroxicam constituted by a succession of layers arranged around an inert, spherical core, prepared in a fluid bed equipment with an inner partition device (wurster). The component elements of the dosage form are:
(1) Inert core,
(2) Active layer,
(3) Insulating layer and
(4) Gastroresistant or enteric coating layer.
The inert cores of dimensions of 600-710 xcexcm or 710-850 xcexcm, constituted by inert excipients, are coated with a layer containing piroxicam mixed with pharmaceutically acceptable inert excipients, making this layer quickly disaggregable. This layer is then coated with an insulating layer of a polymeric nature, which is coated finally with an gastroresistant coating layer of a minimum thickness of 20 xcexcm. The pellets have spherical symmetry and a flat surface, are free from residues of organic solvents and the impurities associated to them and they have a moisture level that guarantees good stability under normal storage conditions. The pellets are placed in hard gelatine capsules and it is in this form that they are administered to patients. The formulations with this composition are characterized in that they do not dissolve in an acid medium, but dissolve quickly at an alkaline pH and present good stability in terms of dosage and in gastroresistance and dissolution assays, when stored for at least 3 years.